Warfarin, tablets 2.5mg 50 pcs

Pharmacodynamics

Warfarin blocks in the liver the synthesis of vitamin K-dependent clotting factors (II, VII, IX, X), reduces their concentration in plasma and slows the clotting process.

The beginning of the anticoagulation action is observed 36-72 hours after the beginning of the drug administration with the development of the maximum effect on the 5th-7th day after the beginning of the drug administration. After discontinuation of the drug activity of vitamin K-dependent clotting factors is restored within 4-5 days.

Pharmacokinetics

The drug is quickly absorbed from the gastrointestinal tract almost completely. Binding to plasma proteins is 97-99%. It is metabolized in the liver.

Warfarin is a racemic mixture, with R- and S-isomers metabolized in the liver by different pathways. Each of the isomers is converted to 2 major metabolites.

The main metabolic catalyst for the S-enantiomer of warfarin is the enzyme CYP2C9 and for the R-enantiomer of warfarin CYP1A2 and CYP3A4. Left-handed warfarin isomer (S-warfarin) has 2-5 times greater anticoagulant activity than right-handed isomer (R-enantiomer), but T1/2 of the latter is longer. Patients with CYP2C9 enzyme polymorphism, including CYP2C9*2 and CYP2C9*3 alleles, may have increased sensitivity to warfarin and increased risk of bleeding.

Warfarin is excreted with the bile as inactive metabolites that are reabsorbed in the GI tract and excreted in the urine. T1/2 is 20 to 60 hours. For R-enantiomer T1/2 is from 37 to 89 hours, and for S-enantiomer from 21 to 43 hours.

Indications

Treatment and prevention of thrombosis and embolism of blood vessels:

acute and recurrent venous thrombosis, pulmonary embolism;
transient ischemic attacks and strokes;
secondary prevention of myocardial infarction and prevention of thromboembolic complications after myocardial infarction;
prevention of thromboembolic complications in patients with atrial fibrillation, lesions of the heart valves or with prosthetic heart valves;
prevention of postoperative thrombosis.

Pharmacological effect

Pharmacodynamics

Warfarin blocks the synthesis of vitamin K-dependent blood coagulation factors (II, VII, IX, X) in the liver, reduces their concentration in plasma and slows down the blood clotting process.

The onset of the anticoagulant effect is observed 36–72 hours from the start of taking the drug, with the development of the maximum effect on the 5–7th day from the start of use. After stopping the drug, restoration of the activity of vitamin K-dependent blood coagulation factors occurs within 4–5 days.

Pharmacokinetics

It is quickly absorbed from the gastrointestinal tract almost completely. Plasma protein binding is 97–99%. Metabolized in the liver.

Warfarin is a racemic mixture, with the R and S isomers being metabolized in the liver by different pathways. Each isomer is converted into 2 main metabolites.

The main catalyst for metabolism for the S-enantiomer of warfarin is the enzyme CYP2C9, and for the R-enantiomer of warfarin CYP1A2 and CYP3A4. The levorotatory isomer of warfarin (S-warfarin) has 2–5 times greater anticoagulant activity than the dextrorotatory isomer (R-enantiomer), but the T1/2 of the latter is greater. Patients with polymorphisms of the CYP2C9 enzyme, including the CYP2C9*2 and CYP2C9*3 alleles, may have increased sensitivity to warfarin and an increased risk of bleeding.

Warfarin is excreted from the body with bile in the form of inactive metabolites, which are reabsorbed in the gastrointestinal tract and excreted in the urine. T1/2 ranges from 20 to 60 hours. For the R-enantiomer, T1/2 ranges from 37 to 89 hours, and for the S-enantiomer from 21 to 43 hours.

Special instructions

A prerequisite for warfarin therapy is the patient’s strict adherence to the prescribed dose of the drug.

Patients suffering from alcoholism, as well as patients with dementia, may be unable to adhere to the prescribed warfarin regimen.

Conditions such as fever, hyperthyroidism, decompensated heart failure, alcoholism with concomitant liver damage can enhance the effect of warfarin. With hypothyroidism, the effect of warfarin may be reduced. In the case of renal failure or nephrotic syndrome, the level of the free fraction of warfarin in the blood plasma increases, which, depending on concomitant diseases, can lead to either an increase or decrease in the effect. In cases of moderate liver failure, the effect of warfarin is enhanced.

In all of the above conditions, careful monitoring of MHO levels should be carried out.

For patients receiving warfarin, paracetamol, tramadol or opiates are recommended for pain relief.

Patients with a mutation in the gene encoding the CYP2C9 enzyme have a longer T1/2 of warfarin. These patients require lower doses of the drug because… When taking normal therapeutic doses, the risk of bleeding increases.

Patients with hereditary galactose intolerance, lactase enzyme deficiency, or impaired absorption of glucose and galactose should not take warfarin. If a rapid antithrombotic effect is necessary, it is recommended to begin treatment with heparin; then combination therapy with heparin and warfarin should be administered for 5 to 7 days until the target IHO level is maintained for 2 days.

To avoid coumarin necrosis, patients with hereditary antithrombotic protein C or S deficiency should first be given heparin. The concomitant initial loading dose should not exceed 5 mg. Heparin administration should be continued for 5–7 days.

In the case of individual resistance to warfarin (very rare), 5 to 20 loading doses of warfarin are required to achieve a therapeutic effect. If taking warfarin in such patients is ineffective, other possible reasons should be established – simultaneous use of warfarin with other drugs, inadequate diet, laboratory errors.

Treatment of elderly patients should be carried out with special precautions, because the synthesis of coagulation factors and hepatic metabolism in such patients is reduced, as a result of which an excessive effect of warfarin may occur.

Active ingredient

Warfarin

Composition

1 tablet contains:

active ingredient:

warfarin sodium 2.5 mg;

excipients:

lactose;

corn starch;

calcium hydrogen phosphate dihydrate;

indigo carmine;

povidone 30;

magnesium stearate

Pregnancy

Warfarin quickly crosses the placenta and has a teratogenic effect on the fetus (nasal hypoplasia and chondrodysplasia, optic nerve atrophy, cataracts leading to complete or partial blindness, mental and physical retardation, and microcephaly) at 6–12 weeks of pregnancy.

May cause bleeding late in pregnancy and during childbirth. The drug should not be prescribed in the first trimester of pregnancy and during the last 4 weeks. The use of warfarin is not recommended during other periods of pregnancy unless absolutely necessary.

It is excreted in breast milk in unmeasured quantities and does not affect the blood clotting activity of the nursing baby. Warfarin can be used during lactation.

Contraindications

established or suspected hypersensitivity to the components of the drug Warfarin;
acute bleeding;
pregnancy (first trimester and last 4 weeks of pregnancy);
severe liver or kidney disease;
acute DIC syndrome;
deficiency of proteins C and S;
thrombocytopenia;
patients at high risk of bleeding, including patients with bleeding disorders;
varicose veins of the esophagus;
arterial aneurysm;
lumbar puncture;
peptic ulcer of the stomach and duodenum;
severe wounds (including operating wounds);
bacterial endocarditis;
malignant hypertension;
hemorrhagic stroke, intracranial hemorrhage.

Side Effects

Very common (>1/10): bleeding.

Often (>1/100,

Uncommon (>1/1000,

Rarely (>1/10000,

From the digestive system: vomiting, nausea, diarrhea.

Bleeding. Over the course of a year, bleeding occurs in approximately 8% of cases among patients receiving warfarin. Of these, 1% are classified as severe (intracranial, retroperitoneal), resulting in hospitalization or blood transfusion, and 0.25% as fatal. The most common risk factor for intracranial hemorrhage is untreated or uncontrolled hypertension.

The likelihood of bleeding increases if MHO is significantly higher than the target level. If bleeding begins with MHO within the target level, there are other underlying conditions that should be investigated.

Necrosis. Coumarin necrosis is a rare complication of warfarin treatment. Necrosis usually begins with swelling and darkening of the skin of the lower extremities and buttocks or (less commonly) elsewhere. Later the lesions become necrotic. In 90% of cases, necrosis develops in women. Lesions are observed from the 3rd to the 10th day of dosing, and the etiology involves a deficiency of antithrombotic protein C or S. Congenital deficiency of these proteins can cause complications, so treatment with warfarin should be started with small initial doses and simultaneously with the administration of heparin. If a complication occurs, warfarin is discontinued and heparin is continued until the lesions heal or scar.

Hand-foot syndrome. A very rare complication during warfarin therapy, its development is typical for men with atherosclerotic diseases. Warfarin is believed to cause hemorrhages in the area of ​​atheromatous plaques, leading to microembolism. There are symmetrical purple lesions on the skin of the fingers and soles of the feet, accompanied by burning pain. After stopping warfarin, these symptoms gradually disappear.

Other: hypersensitivity reactions manifesting as skin rash and characterized by a reversible increase in liver enzyme levels, cholestatic hepatitis, vasculitis, priapism, reversible alopecia and tracheal calcification.

Independent risk factors for the development of serious bleeding during treatment with warfarin are: older age, high intensity of concomitant anticoagulant and antiplatelet therapy, a history of strokes and gastrointestinal bleeding.

The risk of bleeding is increased in patients with polymorphism of the CYP2C9 gene.

Interaction

It is not recommended to start or stop taking medications, or change the dosage of medications taken without consulting your doctor.

When prescribing simultaneously, it is also necessary to take into account the effects of stopping the induction and/or inhibition of the action of warfarin by other drugs.

The risk of severe bleeding increases when taking warfarin simultaneously with drugs that affect platelet levels and primary hemostasis: acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, most NSAIDs (with the exception of COX-2 inhibitors), antibiotics of the penicillin group in high doses.

You should also avoid the combined use of warfarin with drugs that have a pronounced inhibitory effect on the cytochrome P450 system, such as cimetidine and chloramphenicol, when taken for several days the risk of bleeding increases. In such cases, cimetidine can be replaced, for example, with ranitidine or famotidine.

The effect of warfarin may be enhanced when taken simultaneously with the following drugs: acetylsalicylic acid, allopurinol, amiodarone, azapropazone, azithromycin, alpha and beta interferon, amitriptyline, bezafibrate, vitamin A, vitamin E, glibenclamide, glucagon, gemfibrozil, heparin, grepafloxacin, danazol, dextropropoxyphene, diazoxide, digoxin, disopyramide, disulfiram, zafirlukast, indomethacin, ifosfamide, itraconazole, ketoconazole, clarithromycin, clofibrate, codeine, levamisole, lovastatin, metolazone, methotrexate, metronidazole, miconazole (including in the form oral gel), nalidixic acid, norfloxacin, ofloxacin, omeprazole, oxyphenbutazone, paracetamol (especially after 1-2 weeks of continuous use), paroxetine, piroxicam, proguanil, propafenone, propranolol, influenza vaccine, roxithromycin, sertraline, simvastatin, sulfafurazole, sulfamethizole, sulfamethoxazole-trimethoprim, sulfafenazole, sulfinpyrazone, sulindac, steroid hormones (anabolic and/or androgenic), tamoxifen, tegafur, testosterone, tetracyclines, thienylic acid, tolmetin, trastuzumab, troglitazone, phenytoin, phenylbutazone, fenofibrate, feprazone, fluconazole, fluoxetine, fluorouracil, fluvastatin, fluvoxamine, flutamide, quinine, quinidine, chloral hydrate, chloramphenicol, celecoxib, cefamandole, cephalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime, cimetidine, ciprofloxacin, cyclophosphamide, erythromycin, etoposide, ethanol.

Preparations of some medicinal plants (official or informal) can also enhance the effect of warfarin: for example, ginkgo (Ginkgo biloba), garlic (Allium sativum), angelica (Angelica sinensis), papaya (Carica papaya), sage (Salvia miltiorrhiza); and reduce it: for example, ginseng (Panax ginseng), St. John’s wort (Hypericum perforatum).

Warfarin and any St. John’s wort preparations should not be taken at the same time, but it should be borne in mind that the inducing effect of warfarin may persist for another 2 weeks after stopping the use of St. John’s wort preparations. If the patient is taking St. John’s wort preparations, MHO should be measured and discontinuation. MHO monitoring must be careful because… its level may increase when St. John’s wort is discontinued. After this, warfarin can be prescribed.

Quinine contained in tonic drinks can also enhance the effect of warfarin.

Warfarin may enhance the effect of oral sulfonylurea hypoglycemic agents.

The effect of warfarin may be weakened when taken concomitantly with the following drugs: azathioprine, aminoglutethimide barbiturates, valproic acid, vitamin C, vitamin K, glutethimide, griseofulvin, dicloxacillin, disopyramide, carbamazepine, cholestyramine, coenzyme Q10, mercaptopurine, mesalazine, mianserin, mitotane, nafcillin, primidone, retinoids, ritonavir, rifampicin, rofecoxib, spironolactone, sucralfate, trazodone, phenazone, chlordiazepoxide, chlorthalidone, cyclosporine. Taking diuretics in the case of a pronounced hypovolemic effect can lead to an increase in the concentration of clotting factors, which reduces the effect of anticoagulants. In the case of combined use of warfarin with other drugs listed in the above list, it is necessary to monitor MHO at the beginning and end of treatment, and, if possible, after 2-3 weeks from the start of therapy.

Foods rich in vitamin K reduce the effect of warfarin; Decreased absorption of vitamin K caused by diarrhea or laxatives potentiates the effect of warfarin. The most vitamin K is found in green vegetables, so when treating with warfarin, you should eat the following foods with caution: amaranth greens, avocado, broccoli, Brussels sprouts, cabbage, canola oil, chayo leaf, onion, coriander (cilantro), cucumber peel, chicory, kiwi fruit, lettuce, mint, mustard greens, olive oil, parsley, peas, pistachios, red seaweed, spinach greens, spring onions, soybeans, tea leaves (but not tea drink), turnip greens, watercress.

Overdose

The treatment effectiveness indicator is on the border of bleeding development, so the patient may develop minor bleeding (for example, microhematuria, bleeding gums, etc.).

Treatment: in mild cases – reduce the dose of the drug or stop treatment for a short period; for minor bleeding, stop taking the drug until the MHO target level is reached. In case of severe bleeding, intravenous administration of vitamin K, administration of activated charcoal, coagulation factor concentrate or fresh frozen plasma.

If oral anticoagulants are indicated for further use, large doses of vitamin K should be avoided, because Warfarin resistance develops within 2 weeks.

Table 2

Treatment regimens for overdose

MHO level Recommendations In case of minor bleeding Skip the next dose of warfarin and continue on lower doses when the therapeutic MHO level is reached 5–9 Skip 1–2 doses of warfarin and continue on lower doses when the therapeutic MHO level is reached or skip 1 dose of warfarin and give vitamin K in doses of 1–2.5 mg orally >9 Stop warfarin, give vitamin K in doses of 3–5 mg orally Discontinuation is indicated drugs 5–9 (surgery planned) Stop taking warfarin and prescribe vitamin K in doses of 2–4 mg orally (24 hours before planned surgery) >20 or severe bleeding Vitamin K in doses of 10 mg by slow IV infusion, transfusion of prothrombin complex factor concentrates or fresh frozen plasma, or whole blood. If necessary, re-introduce vitamin K every 12 hours.

After treatment, long-term monitoring of the patient is necessary, given that T1/2 of warfarin is 20–60 hours.

Storage conditions

At a temperature not exceeding 25 °C

Shelf life

5 years

Manufacturer

Takeda GmbH, Germany